There is evidence in both human essential hypertensives and spontaneously hypertensive rats (SHR) that biosynthesis of thromboxane A2 (TXA2), a powerful vasoconstricting prostanoid is increased. Based on these circumstantial observations, a group of SHR were treated with the TXA2 synthesis inhibitor 4 feet-(1-YL-imidazol) acetophenone during the developmental phase of their hypertension, i.e., from 4 through 10 weeks of age. At 8 weeks of age systolic blood pressures in the treated group were 140.0 vs 156.6 mmHg in the control group (p less than 0.01) and at 10 weeks of age the separation was even more pronounced: 155.3 vs 184.8 for treated vs control groups (p less than 0.001). The aim of this research proposal is to further explore both the scope and mechanism of this apparently beneficial effect of TxA2 inhibition in hypertension. The plan call for the testing of UK38,485 (Plizer Co.) and OKY1581 (ONO Co.), TxA2 synthetase inhibitors from different chemical classes, during both the developmental and established phases of hypertension in high, normal and low renin rat models. A TxA2 receptor blocking agent will also be tested. These studies will carefully delineate the antihypertensive potential of these agents in various models of experimental hypertension. Other studies are proposed to investigate the biochemical and physiological mechanisms through which these agents lower blood pressure. The methods to be employed for the measurement of protaglandins, catecholamines, and the renin-angiotensin system include radioimmunoassay, radioenzymatic assay, and gas chromatography-mass spectrometry respectively. Blood pressure will be recorded from hypertensive rats utilizing either a tail cuff sphygmomanometer or an intra-arterial catheter connected to a transducer physiograph unit. Other techniques include the in situ perfused mesentery, the isolated perfused kidney, and injection of radioactive microspheres to measure effects on sympathetic neurotransmission, renal function and systemic hemodynamics (cardiac output and regional blood flow) respectively. These experiments may very well provide the basis for a new therapeutic approach to human hypertension.